IHD Dr. Cubeddu handout 2024(1).pdf

Pharmacological Treatment of Ischemic Heart Disease (Coronary Artery Disease). Luigi X. Cubeddu MD. Ph.D. Concepts: Ischemia: decreased blood supply to tissues/organs. Hypoxia: decreased oxygen levels in tissues/organs Ischemia leads to hypoxia. However, there may be hypoxia without ischemia such...

Pharmacological Treatment of Ischemic Heart Disease (Coronary Artery Disease). Luigi X. Cubeddu MD. Ph.D. Concepts: Ischemia: decreased blood supply to tissues/organs. Hypoxia: decreased oxygen levels in tissues/organs Ischemia leads to hypoxia. However, there may be hypoxia without ischemia such as in sleep apnea, anemia, and high altitudes, Chronic Obstructive Pulmonary Disease (COPD), Acute Respiratory Distress Syndrome (ARDS, like in severe COVID). The amount of oxygen that an organ receives depends on blood flow (oxygen travels in the red blood cells bound to hemoglobin), and on the amount of oxygen that the tissue can extract. There are two ways of getting more oxygen: by providing more (increased blood supply/vasodilation) and by extracting more oxygen or being more efficient in using the oxygen. The Coronary flow reserve can be measured by determining how much can coronary blood flow increase above resting blood flow when the coronary arteries are fully dilated (4-6 times greater than resting blood flow). Vasodilation of the coronary blood arteries and arterioles increases blood flow to the heart and the oxygen supply. The heart is very efficient in extracting oxygen, even during resting conditions extracting most of the oxygen (70%) that is supplied. Therefore, for the heart, increasing blood flow is the best way to provide more oxygen. If the increase in blood flow is restricted by atheromatous plaques or by vasospasm, the heart will not have sufficient oxygen and will develop ischemia and hypoxia, leading to symptoms, such as chest pain (acute coronary syndrome), arrhythmias, and even sudden cardiac death. Ischemic Heart Disease (IHD). Angina Pectoris is the primary symptom of IHD and is characterized by chest pain or an anginal equivalent (see below) of cardiac origin. The pain is the consequence of myocardial ischemia and hypoxia (insufficient blood flow and oxygen delivery to the heart muscle). It results from an imbalance between the amount of oxygen required to function (oxygen demand) and the actual amount of oxygen supplied. Note: sudden pain, pressure, tightness, or discomfort in the chest, shoulders, arms, neck, back, upper abdomen, or jaw is an anginal equivalent, as are sudden shortness of breath and fatigue. Any patient presenting any of these symptoms should call 911 and seek immediate medical care. The oxygen (blood supply) reaches the heart muscle and conduction system through the coronary arteries; therefore, the coronary blood flow and the concentration of hemoglobin in the blood are important determinants of the amount of oxygen that is delivered to the heart. Atherosclerotic plaques obstructing the large epicardial coronary arteries and thus decreasing blood supply are the most common cause of ischemic heart disease. Oxygen demand (oxygen requirements) depends on the heart rate (how fast the heart is beating), the strength of contraction (contractility: how strong the heart is pumping), the load (pressure) against which the heart must pump blood (afterload: aortic pressure), and the tension generated by the stretch of the ventricular muscle (preload). Myocardial Oxygen Consumption depends on 1. Heart rate (faster HR = greater 02 consumption) 2. Myocardial inotropic state (contractility; stronger = greater 02 consumption) 3. Preload: cardiac muscle tension during diastole (preload). The greater the end- diastolic volume and pressure, the greater the tension created on the muscle, and the oxygen consumption. Venoconstriction increases venous return and increases preload. 4. Afterload: The myocardial wall tension generated during systole depends on the aortic pressure and the BP. To send the blood into the arteries, the left ventricle should generate a pressure that must be higher than the pressure in the aorta, otherwise, the blood will not leave the ventricle. This requires lots of power and thus lots of oxygen to generate ATP for the cardiac contraction. The higher the aortic pressure and the BP, the greater the afterload and the amount of oxygen used. I. Classical angina or effort-induced angina. It presents as a short episode of chest pain due to transient myocardial ischemia precipitated by exertion, meals, cold exposure, and /or emotional stress. It is usually of short duration (1-5 min) and improves with rest and/or with sublingual nitroglycerin. Atherosclerosis is the most frequent cause of this disease, due to obstruction of the coronary arteries. Plaques obstruct the flow of blood, reducing the supply of blood to the heart. The chest pain is triggered by an increase in oxygen requirements in the presence of a fixed obstruction in one or several large epicardial coronary arteries. If the heart oxygen requirements are low (i.e., the subject is resting), the amount of blood flow through the partially obstructed artery may be sufficient, thus there will be no chest pain while resting. However, if the oxygen demand of the myocardium increases (i.e., walking, running, stress, fever, beta-agonists, inotropes, anemia, reflex increases, etc.), then the blood supply becomes insufficient, manifesting in an episode of angina (chest pain). During ischemia ATP is degraded to adenosine, which acts on A1 receptors present in sensory cardiac afferent nerve endings, signaling pain. The angina pattern may be that of Stable angina, which means that the chest  pains are highly predictable with a certain level of physical activity and that the chest pains are of short duration. Generally, the chest pain can be reproduced during a Stress test, and the ischemia can be observed by changes in the ECG. A continuous ECG is obtained during the stress test. II. Variant angina (rest angina, Prinzmetal angina, Vasospastic angina): In its pure form, the pain develops during resting conditions, without any evidence of an increase in myocardial oxygen consumption. It is not triggered by physical activity. It is due to a coronary vasospasm (vasoconstriction) and is treated with coronary vasodilators. Commonly these patients do not have obstructions on the large epicardial coronary arteries. Provocative testing is often employed to determine if the patient has this type of angina. Hyperventilation, smoking, cold weather, and emotional stress are triggering factors. Dysfunction of the endothelium plays a key role in determining vasospastic angina. III. Mix forms of Angina: characterized by both obstruction and vasospasm. Patients may complain of effort-induced chest pain and chest pains at rest. IV. Microvascular angina or syndrome X: angina episodes with ST elevation, mostly in post-menopausal women, with normal large coronary arteries in the angiography. Due to alterations of the small arterioles that are the resistance blood vessels. More frequent in diabetics, hypertensives, and collagen vascular diseases. V. Silent angina: Is characterized by ischemic episodes not associated with chest pain. In general, there is a direct relationship between the number of chest pains (angina attacks) and the number of silent ischemia episodes. Holter monitoring is the best test to determine the presence of silent ischemia. The Holter allows continuous monitoring of the patient's ECG, capturing the ischemic episodes, which are defined as transient ST depression of 1 mm or above lasting for at least 1 min. Commonly over 70% of these episodes are silent. Total ischemic time: symptomatic (chest pains) ischemia + silent ischemia. NOTE: chronic IHD, with many episodes of cardiac hypoxia (ischemia) through the years, can irreversibly damage the cardiac muscle and the cardiac conduction system leading to Heart Failure (a weak /or stiff heart) and arrhythmias (atrial fibrillation, ventricular tachycardia, ventricular fibrillation, sudden cardiac death). Acute Coronary Syndrome is an emergency. Unstable angina, NSTEMI and STEMI. Are characterized either by increased frequency and severity of angina attacks (chest pains), an episode of rest angina that lasts more than 20 min, new-onset  angina (new onset chest pain) or marked sudden shortness of breath. It is not relieved by sublingual NTG. ECG and biomarkers define the type of ACS. Unstable angina is defined by no ST segment changes or ST segment depression without increases in biomarkers, indicating absence of tissue necrosis. STEMI or ST elevation myocardial infarction is characterized by persistent anginal symptoms, ST segment elevation and increase levels of biomarkers, indicating tissue necrosis. NSTEMI or non-ST segment elevation myocardial infarction, is characterized by persistent anginal symptoms, no ST segment elevation and increase levels of biomarkers, indicating tissue necrosis. An ACS Is commonly due to the rupture of an atherosclerotic plaque followed by platelet adhesion and aggregation, with the subsequent vasoconstriction and decreased coronary blood flow. The coagulation cascade is activated leading to the formation of a clot that may fully block the blood flow. Soft plaques are usually the ones that fissure leading to platelet aggregation and clot formation, which if untreated may cause severe ischemia. Complete obstruction would lead to acute tissue necrosis (myocardial infarction; MI), often associated with severe and fatal arrhythmias (due to the lack of oxygen, no ATP formation, inhibition of cellular active transports, and cell depolarization that can trigger the arrhythmias). ACS fail to respond to sublingual nitroglycerin. Unstable angina is an emergency. The changes in the ECG are important. The ST segment of the ECG is used for diagnosis. STEMI: is described as a form of unstable angina, often presenting as chest pain not relived with sublingual NTG, an ECG showing ST segment elevation, and laboratory exams showing increases in biomarkers of myocardial tissue damage. Biomarkers: High-sensitivity troponins. Increased biomarkers in the blood suggest tissue necrosis (cardiac proteins from tissue damage pass to the blood). Patient management. We are treating a disease of which angina and ACS are symptoms. The disease is coronary artery disease or CAD, which may lead to ischemia (ischemic heart disease) whose symptoms may be angina stable and/or ACS. CAD is most frequently due to atherosclerosis of the coronary arteries. Atherosclerosis is produced by the deposition of oxidized LDL-cholesterol in the wall of the coronary arteries, which leads to inflamxmation of the coronary arteries and the formation of atherosclerotic plaques. Therefore, the treatment of IHD comprises: 1. Treatment of the atherosclerosis (prevention and treatment) a. Lifestyle, Statins, glucose control, anti-HT, weight control. b. Clot formation: aspirin c. Anti-inflammatory therapy: colchicine, statins d. Stents/ revascularization (PCI, percutaneous coronary intervention; CABG). e. ACS treatment 2. Treatment of the symptoms, namely angina and ACS.  a. Beta-blockers b. CCB c. Organic nitrates d. Ranolazine e. Others. I. Primary prevention: Non-Pharmacological Treatment of Coronary Artery Disease (IHD). Prevention is the key. The Risk factors are a family history of premature coronary artery disease, obesity, sedentary lifestyle, cigarette smoking, hypercholesterolemia, diabetes mellitus, and hypertension. Patients with angina require smoking cessation, hypertension control, diabetes mellitus control, obesity management, and serum lipids control. NOTE: commonly these patients are treated with enteric-coated aspirin or clopidogrel, statins, anti-HT drugs ACEI or ARBs, beta-blockers and/or calcium channel blockers, anti-diabetic drugs (SGLT2 inhibitors), and weight-losing drugs (semaglutide). DM is associated with a high incidence of atherosclerotic vascular disease. IHD is very common in DM. Strict glycemic control in patients with Diabetes Mellitus (DM) is required. NOTE: Because patients with DM may have sensory nerve damage, silent ischemia, and even a silent myocardial infarction are more frequent in Diabetic than in non-diabetic patients. Pharmacological Treatment of Effort-induced angina (classical angina). Beta- blockers Organic nitrates Calcium Channel Blockers Ranolazine Ivabradine Nicordanil Aspirin ± Clopidogrel/rivaroxaban Statins (Lipid-lowering drugs) II. Surgical procedures. PCI + Stent placement (medicated/non-medicated stents) (DES or BMS) Open chest surgical reperfusion (Coronary artery bypass; CABG) Heart Transplantation (severe disease associated with severe CHF) DRUGS USED TO TREAT CHRONIC - STABLE IHD. Beta-blockers reduce BP and decrease sympathetic stimulation to the heart, inducing negative chronotropic (bradycardia), negative dromotropic (slower conduction velocity), and negative inotropic (reduced contractility) effects. Therefore, beta-blockers decrease myocardial oxygen consumption. The reduction in oxygen consumption occurs at rest, but mainly during physical activity. Therefore, on a beta-blocker the patient will be able to walk without experiencing chest pain. The beta-blocker prevents chest pain (ischemia) because it dampens the increases in heart rate, contractility, and BP induced by physical activity and stress. For example, an untreated patient develops chest pain after waking 200 yards. At this time, his HR increased from 75 beats/min (resting) to 118 (time of pain) and his BP raised from 130/89 mmHg to 158/92. After a diagnosis of classic angina was made, the patient was started on metoprolol. Two weeks later, the same walk did not produce chest pain. On metoprolol, the patient’s baseline HR was 50 and to 63 beats/min at the end of the walk, and the baseline BP was 122/80 and 130/82 at the end of the walk. The beta- blocker lowered the resting HR and BP and reduced the increases in HR and BP induced by the exercise. When the patient was without a beta-blocker the chest pain developed when his heart rate was 118 and his BP 158/92; now, on the blocker, the same walk increased the HR to only 63 beats/min and the BP 130/82. NOTE: If the patient on a beta-blocker increases the intensity and duration of the exercise to such an extent that his heart rate reaches 118 beats/min and his BP 158/92 mmHg, the patient would most likely experience chest pain. Consequently, any drug or activity that increases the HR, cardiac contractility, BP, and myocardial oxygen consumption (either directly or reflexively) may trigger and aggravate angina. Vasodilators lower BP and often lead to reflex stimulation of the heart, which may aggravate myocardial ischemia (i.e., rapid BP drop with hydralazine, or a dihydropyridine, such as nifedipine). NON-ISA beta-blockers are the drugs of choice to treat effort-induce angina. The patient’s characteristics will determine which beta-blocker to use. Therefore, as monotherapy, and in the presence of a good cardiac function, beta-blockers are the drugs of choice in patients with effort-induced angina. Selective beta-blockers should be preferred over non-selective beta-blockers for the treatment of patients with coronary artery disease (angina pectoris). Understand that this treatment is purely symptomatic; beta-blockers reduce the number of ischemic attacks and chest pains but do not eliminate the obstruction or the cause of the coronary obstruction. However, by preventing the angina episodes (preventing ischemic episodes), they avoid further cardiac damage due to the ischemia. In patients with effort- induced angina, a combination of metoprolol and ivabradine reduced HR by 20 beats/ min, decreased by 8-fold the number of angina attacks and NTG use, and improved quality of life. Ivabridine acts on the SA node to decrease HR. Beta-blockers do not DILATE coronary arteries; in fact, beta-blockers may worsen vasospasm, and should not be used in pure forms of Variant (rest, vasospastic) angina. B. ORGANIC NITRATES (NITROSO-VASODILATORS) in IHD. Sublingual nitroglycerin (NTG) is fundamental in the treatment of angina. NTG can be used for acute relief of pain and prophylactically before activities known to trigger an anginal episode. Nitroglycerin (Sublingual, Ointment, Transdermal patch). Isosorbide dinitrate (IR and ER). Isosorbide mononitrate (IR and ER) MOA: these agents are di-nitrated by the glutathione-organic nitrate reductase forming Nitric Oxide (NO). The NO penetrates the smooth muscle cells activating the enzyme guanylyl cyclase that is found in the cytoplasm. This enzyme forms cGMP from GTP. The increase in cGMP produces smooth muscle relaxation, vasodilating the blood vessels. These drugs are also known as NO donors! “At low doses, the organic nitrates are selective VENODILATORS. These agents dilate systemic veins and pulmonary veins, reducing venous return. They decrease preload, which means that the end-diastolic volumes and pressures are decreased, in turn decreasing the myocardial oxygen consumption” “At higher doses: organic nitrates induce, in addition, arteriolar vasodilation, decreasing total peripheral resistance and BP. Therefore, these drugs may also reduce afterload, further decreasing myocardial oxygen consumption”. However, if the arteriolar vasodilation were excessive, then reflex increases in heart rate and contractility may ensue, increasing myocardial oxygen consumption. Organic Nitrates are CORONARY VASODILATORS. Organic nitrates dilate the large coronary arteries, increasing the blood flow to the ischemic regions (redistribution of blood flow), and eliminating vasospasm if present. The major immediate mechanism by which organic nitrates improve an acute episode of effort-induced angina is by decreasing MYOCARDIAL OXYGEN CONSUMPTION due to vasodilation and decreased preload. They also favor a greater blood flow to the ischemic areas. Pharmacokinetics. The isosorbide mononitrate is less metabolized, has better bioavailability, and longer half-life than the di- and tri-nitrated compounds. NTG (nitroglycerine) suffers extensive hepatic metabolism and a first-pass effect. NTG: sublingual NTG has a t1/2 of 1-3 minutes. Can be given PO as a sustain-release formulation. NTG ointments (skin absorption) are absorbed in 0.5-1 hr and last 4-6 hrs. NTG disks are also available. NTG is available for intravenous administration. Isosorbide mononitrate: Sublingual t1/2 45 minutes and it reaches plasma within 6 minutes. Orally peaks 1-1.5 hrs and lasts 4-6 hrs. Oral isosorbide-mononitrate has a greater bioavailability than NTG and isosorbide-dinitrate. For acute angina attacks: sublingual NTG or isosorbide-dinitrate can be used. For example, 0.3 mg sublingual NTG, which could be repeated after 15 min if pain is still present. Tolerance and dependence occur during chronic treatment with organic nitrates. Continuous and prolonged exposure to organic nitrates produces tolerance to its effects. Therefore, intermittent therapy has been recommended, i.e., Interrupt treatment 8-12 hr each day Omit night dose Remove cutaneous dose at bedtime Dose at 7 am and 2 pm. NOTE: patients may need additional medications to cover the nitrate-free intervals. Dependence is another problem observed with these agents. Worsening of angina often occurs when nitrate levels are low and rebound of angina attacks may occur during nitrate-free intervals. Therefore, patients must be advised about tolerance and dependence during chronic treatment with organic nitrates. Side Effects. Most side effects are due to their vasodilatory effect, i.e., headache, dizziness, postural hypotension, flush (redness and warmth), and nausea. Sublingual drugs should be placed when the patient is sitting or lying down. Standing increases the likelihood of developing postural hypotension. Ethanol worsens the side effects of organic nitrates, possibly by enhancing vasodilation. Unwanted reflex tachycardia and increased myocardial oxygen consumption may occur if the dose is too high or absorption is too fast. Serious drug interactions: with PDE-5 inhibitors (Sildenafil, Tadalafil, Vardenafil, Avanafil) and with Riociguat (Adempas, Bayer). Riociguat stimulates guanylate cyclase to increase the production of cGMP. PDE-5 inhibitors decrease the inactivation of cGMP, so cGMP accumulates. High levels of cGMP produce excessive vasodilation. Severe hypotension may occur in patients taking organic nitrates which increase cGMP levels, together with PDE5 inhibitors or Riociguat. C. CALCIUM CHANNEL BLOCKERS. Long-acting formulations of heart rate-slowing CCBs are used to control effort-induced angina in patients in whom Beta Blockers are contraindicated, or if symptoms cannot be controlled despite the use of BB and ON. Short-acting DHPs should be avoided, due to the risk of acute hypotension and reflex increases in HR and contractility. Calcium entry through voltage-dependent calcium channels plays a fundamental role in determining action potentials in the Sino-atrial node (SA node) and in the Atrioventricular node (AV node). At the SA node, blockade of these channels with CCB slows down heart rate. At the AV node, blockade of these channels slows down AV conduction, increasing the time that it takes for an action potential (an impulse) to pass from the atria to the ventricles (manifested by a longer PR interval in the ECG). In the Ventricle (myocardium, heart muscle), the voltage-dependent calcium channels open during the plateau period of the action potential, and large amounts of calcium enter the muscle cells. This calcium leads to muscle contraction. CCBs reduce calcium entry, decreasing myocardial contractility. CCBs dilate the coronary arteries (coronary vasodilators). CCBs dilate the systemic arterioles with the consequent reduction in total peripheral resistance and BP (anti-hypertensives). The reduction in BP, if rapid and of a large magnitude activates the baroreceptor reflex leading to compensatory increases in sympathetic nervous system activity. The DHP-CCBs are stronger vasodilators than verapamil and diltiazem; whereas, verapamil and diltiazem have stronger cardiac effects than DHP-CCBs. Therefore, the DHP-CCBs increase heart rate and have no anti-arrhythmic actions. Care should be exerted when using a rapidly acting DHP because of the possible increase in myocardial oxygen consumption. If needed, may be used combined with a beta- blocker. Verapamil and diltiazem lower BP with little or no reflex tachycardia. Both, verapamil and diltiazem slow AV conduction (first-degree AV block is often seen) and contractility is generally depressed. These two agents are more cardiac depressants than DHPs and are used as anti-arhythmics. Verapamil and diltiazem slow the ventricular rate in patients with rapid atrial arrhythmias, such as atrial fibrillation and atrial flutter. CCB use in effort-induced angina. Verapamil and diltiazem are arteriolar vasodilators that induce little to no reflex increases in heart rate and contractility. The arteriolar vasodilation decreases afterload and thus reduces myocardial oxygen consumption. The reduction in HR and contractility also decreases myocardial oxygen consumption. Therefore, these two CCBs could be used alone, as monotherapy in effort-induced angina, because they reduce myocardial oxygen consumption. In addition, they are coronary vasodilators. DHP and non-DHP-CCBs are coronary vasodilators. The CCBs dilate the coronary arteries and prevent or relieve coronary vasospasm. This action explains the efficacy of CCB in vasospastic angina (rest or variant angina). It is important to emphasize that the distal coronary arterioles (smaller coronary arterioles) are far less responsive to vasodilators such as nitroglycerin than the proximal, larger, coronary arteries. CCBs are effective vasodilators also for the smaller, more distal coronary arterioles. In addition to CCB or Organic Nitrates, intracoronary adenosine, and sodium nitroprusside may also be used for spasms of the small coronary vessels. As indicated before, there are differences between the CCB. Even within the DHP groups, some agents are more cardiac selective or vascular selective than others. For example, felodipine has greater vascular specificity and has little or no negative inotropic action; consequently, with felodipine, there is more reflex cardiac stimulation. Isradipine, for example, decreases peripheral resistance but in addition, inhibits the SA node; therefore, it lowers BP with little or no reflex tachycardia. Because of its slow absorption and very long half-life (36 hours), amlodipine lowers BP with less reflex stimulation to the heart. Amlodipine does not need a sustained-release formulation; whereas most CCBs are available in sustained-release formulations. In summary, as monotherapy, non-DPHs –CCB (verapamil and diltiazem) are preferred over the DHPs-CCB for stable angina, unless contraindicated, i.e., the presence of AV block. Note: because most of these patients are receiving beta-blockers for their treatment, DHP-CCB (nifedipine, nicardipine, amlodipine) could be used, because of their greater effects on afterload, and because, the beta-blockers would prevent the unwanted reflex increases in HR and contractility. Besides, the combination of beta-blockers and verapamil or diltiazem may lead to potential cardiac depression. NOTE: Anginal symptoms in patients with vasospastic angina (Prinzmetal angina) can be treated with CCB, with or without organic nitrates. Supplemental Vitamin E added to a CBB importantly reduces anginal attacks. CCB Side Effects: Due to Vasodilation: headaches, flushing, dizziness, palpitations if BP drops too fast too much. Reflex tachycardia and increased contractility with DHPs Constipation: mainly with verapamil. AV Block: verapamil and diltiazem. Worsening of CHF (because of cardiac depressant action). CHECK for DIT: Verapamil and diltiazem are known to be CYP3A4 and p- glycoprotein inhibitors. Simvastatin is extensively metabolized by CYP3A4. Therefore, concomitant use of simvastatin and verapamil can increase simvastatin plasma concentration levels, resulting in a higher risk of rhabdomyolysis, a serious adverse drug reaction. Dose adjustments are needed when given together with either, abigatran, colchicine, ivabradine, digoxin, anti-arrhythmics, or cardiac depressants. D. RANOLAZINE (Ranexa) Approved to treat effort-induced angina. It should be used in combination with other antianginal agents. It is not intended for the treatment of an acute attack of angina. Ranolazine improves cardiac muscle oxygen utilization. This is achieved as  follows: ranolazine inhibits the late phase of the sodium current (late INa). Normally there is minimal to no late sodium current. After the large entry of sodium into the cardiac cells responsible for the depolarization of the cells, sodium channels are inactivated, and no more sodium gets in. After which, there is a small entry of sodium, called the late INa. In disease states, such as ischemia and heart failure, the late INa is increased. This causes additional entry of sodium, increasing the amount of intracellular sodium. This sodium excess is eliminated from the cells in exchange for calcium, increasing the amount of calcium in the cell. The increase in intracellular calcium affects the electrical and mechanical cell function, increasing oxygen consumption by the cardiac muscle. Inhibition of late INa with ranolazine decreases the entry of sodium into the cells, decreases intracellular sodium and prevents calcium overload, improving diastolic relaxation, and decreasing myocardial oxygen consumption. Ranolazine increases exercise duration and time to onset of exercise-induced angina (chest pain or ischemia), decreases the number of angina attacks, and the use of nitroglycerine. Is often combined with atenolol, NTG, and/or amlodipine. Ranolazine may have antiarrhythmic actions. Patients treated with ranolazine had fewer episodes of ventricular tachycardia, supraventricular tachycardia, new-onset atrial fibrillation, or ventricular pauses lasting at least 3 seconds. NOTE: Ranolazine prolongs the QTc interval of the ECG. To prevent the development of Torsade de Pointes, avoid using ranolazine in combination with other drugs that prolong the QT interval of the ECG. Ranolazine is a substrate of CYP3A4. It should be avoided in combination with CYP3A4 substrates and inhibitors, such as simvastatin, verapamil, diltiazem, or fluconazole. Note adverse interactions have been described when ranolazine is combined with antiretrovirals such as darunavir-cobicistat. The most reported side effects are dizziness, headache, constipation, and nausea. E. NICORDANIL is a potassium channel activator and a NO donor. The plasma membrane adenosine triphosphate (ATP)-sensitive potassium channel is activated by nicorandil, leading to the opening of the potassium channels, increasing potassium efflux and membrane hyperpolarization. This relaxes the smooth muscle, leading to vasodilatation of arterioles and large coronary arteries. Besides, Nicordanil has a nitrate group on its molecule. It provides NO, leading to venodilation through the stimulation of guanylate cyclase. In summary, nicordanil induces arterial and veno-dilation, decreasing afterload and preload, and relaxes the coronary arteries. Is effective in the treatment of Angina Pectoris. It is particularly useful in patients with refractory or unstable angina. It is of interest to note that the increase in potassium efflux speeds up the repolarization, shortening the duration of the action potentials, and preventing excessive calcium entry. Preventing intracellular calcium overload confers cardio-protection. Nicordanil is dosed PO, BID. Headache, dizziness, orthostatic symptoms, flushing, and palpitations are the most common side effects, that decrease with time. NOTE: Mouth, stomach, rectal, eye, and skin ulcers have been reported, although this is a rare side effect. COLCHICINE. Anti-inflammatory Stabilizes the atherosclerotic plaque by reducing inflammation. Recent FDA approval: 0.5 mg QD, to reduce the risk for MI, stroke, need of revascularization, and CV death in adult patients with established atherosclerotic disease or with multiple risk factors for CV disease. Is given on top of standard prevention therapies. Is mainly used in patients with clinical evidence of inflammation; i.e., increased plasma concentrations of C-reactive protein of 2 or greater mg/L Can be used alone or in combination with cholesterol-lowering medications. The inflammatory response is mainly induced by OxLDL and cholesterol crystals: favoring the formation and activation of NLRP3 inflammasomes in macrophages, and increasing the expression of the inflammatory cytokines IL1β, IL-6, and C-reactive protein. Colchicine decreases the levels of IL-1β, thereby inhibiting the inflammatory response in atherosclerosis. Colchicine should be avoided or the dose should be lowered or discontinued when combined with CYP3A4 and P-gp inhibitors. E. COMBINED THERAPY IN IHD. Stable, Effort-induced angina: A combination of a beta-blocker + organic nitrates + CCB may be required for more severe cases of classic-effort-induced angina. An example of triple therapy would be metoprolol, isosorbide-monitrate, and amlodipine orally, plus sublingual NTG for acute attacks. Ranolazine may be added if needed. Combinations of BB and ivabradine have shown great benefits. F. Medications used after a myocardial infarction. Beta-blockers ACEI Antithrombotic Anticoagulants F. PCI and STENT placement. A coronary stent is a tube-shaped device placed in the coronary arteries to keep the arteries open. The stent is placed during a percutaneous coronary intervention (PCI). There are two main complications with stent placement: thrombosis and stenosis. Intracoronary thrombosis and risk of myocardial ischemia or infarction may occur soon after PCI with stent implantation. Trauma to the coronary endothelium (with the exposure of tissue factors to blood) and placement of a metal stent (which is a procoagulant) are causative. Stent thrombosis can be a life-threatening event. Drug-eluting stents (DES) are used for most PCI with stenting. The DESs are composed of a metallic stent, a polymer, and a pharmacologic agent (typically an immune- suppressant and/or anti-proliferative compound). The goal of the DES is to minimize the restenosis of the stented artery. The stenosis happens by inflammation and cellular proliferation. Sirolimus, everolimus, zotarolimus, and ridaforolimus are compounds adsorbed on the polymer and are gradually released. These agents are cell cycle inhibitors, inhibit the proliferation of the vascular smooth muscle, and prevent vascular intimal thickening. On average, the 5-years incidence of restenosis is around 6%. To minimize the risk of thrombosis, all patients planning PCI with stent placement must receive periprocedural aspirin with ticlopidine or clopidogrel on top of aspirin therapy. Typically, aspirin is given as 75 to 100 mg daily to all patients scheduled for stenting. For patients not previously taking aspirin, a single loading dose of 300 to 325 mg is used. For clopidogrel, 600 mg as a single loading dose 24 hours or more (but at least two hours) before the procedure. Followed with 75 mg daily until the PCI. After the decision to proceed with PCI, unfractionated heparin is used. The optimal duration of dual antiplatelet therapy (DAPT) after placement of intracoronary stents in stable patients depends on patient-specific ischemic and bleeding risks. For many patients, a course of DAPT for 6 to 12 months is a reasonable duration. For patients at higher bleeding risk, a shorter course of DAPT followed by antiplatelet monotherapy may be appropriate, while for patients at higher ischemic risk, a longer course of DAPT may be reasonable. Before PCI: Loading aspirin 325 + clopidogrel (300-600 mg). After PCI: Aspirin 81 indefinitely, clopidogrel 75 mg x 12 m, pasugrel 12 month. Only less duration if high risk of bleeding. BMS or DES: optimal 12-month DAPT. Minimal 1 month for BMS, and minimal 6 months for DES. CABG: 12 months DAPT